PL87801B1 - Amino pyrimidines[us3635978a] - Google Patents

Amino pyrimidines[us3635978a] Download PDF

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Publication number
PL87801B1
PL87801B1 PL1970166422A PL16642270A PL87801B1 PL 87801 B1 PL87801 B1 PL 87801B1 PL 1970166422 A PL1970166422 A PL 1970166422A PL 16642270 A PL16642270 A PL 16642270A PL 87801 B1 PL87801 B1 PL 87801B1
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Poland
Prior art keywords
acid
amino
hydroxy
group
compound
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PL1970166422A
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Polish (pl)
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University Of Strathclyde Te Glasgow Grootbrittannie
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Publication of PL87801B1 publication Critical patent/PL87801B1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D239/00Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48Two nitrogen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D475/00Heterocyclic compounds containing pteridine ring systems
    • C07D475/02Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
    • C07D475/04Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Indole Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Furan Compounds (AREA)

Abstract

1303171 Pteridine derivatives STRATHCLYDE UNIVERSITY OF 23 Jan 1970 [28 Jan 1969] 3301/70 Heading C2C The novel pteridine derivative tautomeric forms or salts thereof are prepared by a light stage synthesis, the steps being (1) condensation of phthalic anhydride with 2- aminoisobutyric acid, to form N-phthalyl-2- aminoisobutyric acid (II), (2) formation of the acid chloride, (3) reaction of the acid chloride with diazomethane to form 1 -diazo-3-methyl-3- plitholimido-buton -2 -oae (IV) (4) hydrolysis of the diazo group to primary hydroxyl group (V), (5) hydrolysis of the imide group to yield 3- amino - 1 - hydroxy - 3 - methylbutan - 2 - o4e VI as its hydsochloride, (6) formation of the semicarbazone VII, (7) condensation at the primary amine group with 2-amino-4-chloro-6- hydroxy - 5 - nitropyrimidine, (8) reductive cyclization to yield I above. Pharmaceutical compositions of compound I or, pharmaceutically acceptable salts thereof with the usual excipients show anti-microbial activity when administered parenterally or orally. [GB1303171A]

Description

Przedmiotem wynalazku jest sposób wytwarza¬ nia nowej 2-amiiino-4-i(l/,l'-dwumetylo-3,-hydroksy- -acetonylo)-aminjO-6-hydroksy-5^nitropirymidyny o wzorze 1. Zwiazek ten jest produktem wyjsciowym do wytwarzania 2-amino-4-hydroksy-6-hydroksy- 5 -metylo- 7,7-dwumetylo- 7,8 - dwuwodoropterydy- ny, bedacej cennym srodkiem bakteriostatycznym.Sposobem wedlug wynalazku 2-amino-4-(l',l'- -dwumetylo-3'-hydroksyacetony!lo)- amino-6-hydro- ksy-5-niitropirymidyne wytwarza sie dzialajac kwa- 10 sem na semikarbazon ketonu pirymidynyloamino- wego o wzorze 2. Stosuje sie w tym celu kwas 0 umiarkowanej mocy, zwlaszcza kwas organiczny, np. kwas trójfluorooctowy lub benzenosulfonowy, albo kwas mineralny, korzystnie rozcienczony, np. 15 rozcienczony kwas solny lub siarkowy.Reakcje prowadzi sie korzystnie w temperaturze wrzenia mieszaniny reakcyjnej w ciagu kilku do kilkunastu minut, po czym mieszanine chlodzi sie, przesacza i przesacz zobojetnia, korzystnie wodóro- 20 tlenkiem amonowym. Wytracony zwiazek o wzorze 1 odsacza sie i oczyszcza znanymi sposobami.Zwiazek o wzorze 2, bedacy produktem wyjscio¬ wym w procesie prowadzonym sposobem wedlug wynalazku, jest zwiazkiem nowym. Wytwarza sie 25 go latwo przez reakcje semikarbazonu 3-amino-l- -hydroksy-3-metylobutanonu-2 lub jego soli, ko¬ rzystnie chlorowodorku o wzorze 3, z 2-amino-4- -chlorowco-6-hydroksy-5-nitropirymidyna. Reakcje prowadzi sie w obecnosci srodka wiazacego kwas, 30 takiego jak np. weglan sodowy lub trzeciorzedowa amina, np. trójetyloamina.Zwiazek o wzorze 3 jest równiez zwiazkiem no¬ wym i wytwarza sie go przez dzialanie semikarba- zydem lub jego sola na 3-amino-l-hydroksy-3-rne- tylobutanon-2 lub jego sól, korzystnie chlorowodo¬ rek o wzorze 4.# Reakcje prowadzi sie korzystnie w obecnosci substancji buforowej, np. octanu lub weglanu sodowego.Zwiazek o wzorze 4 jest takze zwiazkiem nowym i otrzymuje sie go w ten sposób, ze.na 1-hydrok- sy-3-metylo-3-ftaloimidobutanon-2 o wzorze 5 dzia¬ la sie kwasem, korzystnie mocnym kwasem, ta¬ kim jak kwas solny, bromowodorowy lub siarko¬ wy.Zwiazek o wzorze 5 jest równiez zwiazkiem no¬ wym i wytwarza sie ,go dzialajac kwasem na 1- -dwuazO'-3-ftaloi:midobutainon-2 o wzorze 6. Jako kwas stosuje sie korzystnie rozcienczony kwas mi¬ neralny, zwlaszcza rozcienczony kwas siarkowy.Zwiazek o wzorze 6 jest takze zwiazkiem nowym i wytwarza sie go na przyklad przez reakcje dwu- azometanu z chlorkiem kwasu N-ftalilo-2-amino- izomaslowego, bedacego zwiazkiem znanym. Ko¬ rzystnie stosuje sie nadmiar dwuazometanu, np. ilosc dwukrotnie wieksza od wynikajacej z obli¬ czen stechiometrycznych, w celu zwiazania kwasu pozostajacego podczas reakcji.Przyklad. Mieszanine 6,0 g chlorowodorku semikarbazonu ketonu pirymidynyloaminowego o 87 80187 801 wzorze 2 i 100 ml 2n kwasu solnego utrzymuje sie w stanie wrzenia pod chlodnica zwrotna w ciagu minut, a nastepnie chlodzi sie i przesacza. Do przesaczu wkrapla sie mieszajac wodorotlenek amonowy o gestosci 0,880 az do uzyskania odczynu 5 obojetnego, po czym odsacza sie wydzielona 2-ami- no-4-(l'.l/-dwumetyilo-3'-hydroksyaeetonylo) -ami- no-6-hydroksy-5-nitropirymidyne i przemywa wo¬ da, etanolem i eterem. Otrzymuje sie produkt o barwie zóltawobialej, o temperaturze topnienia 10 218°C Stosowany w tym przykladzie jako produkt wyjsciowy zwiazek o wzorze 2 wytwarza sie w nastepujacy sposób* Roztwór dwuazometanu w ete¬ rze, nie zawierajacy alkoholu, otrzymany przez rozpuszczenie 136 g preparatu Diazald w 950 ml 15 eteru, wkrapla sie do mieszaniny zawierajacej roz¬ twór 40,9 g wodorotlenku potasowego w 70 ml wody, 240 ml glikolu dwuetyilenowego i 70 ml ete¬ ru, ogrzanej do temperatury 65—70°C na lazni wodnej. Powstajacy dwuazometan oddestylowuje 20 sie powoli traktuje roztworem 51,1 g chlorku kwa¬ su N-ftalilo-2-aminoizomaslowego w 700 ml eteru.Mieszanine wytrzasa sie i pozostawia na okres no¬ cy w temperaturze pokojowej, po czym odparo¬ wuje eter pod zmniejszonym cisnieniem, otrzy- 25 mujac l-dwuazo-3-metylo-3-ftalimidobutanon-2 ó wzorze 6 w postaci krysztalów o barwie jasnozól- tej. 50 g otrzymanego produktu miesza sie z 500 ml 0,5n kwasu siarkowego i ogrzewa do temperatury 30 80°C, zapoczatkowujac proces hydrolizy. Po ustaniu wydzielania sie gazu mieszanine wlewa sie do 1 litra lodowatej wody, odsacza otrzymany 1-hydrok- sy-3-metylo-3-ftalimidofoutanon-2 o wzorze 5 i przemywa 50 ml wody, a nastepnie przekrystali- 35 zowuje z wodnego roztworu etanolu, dodajac wegla aktywowanego. Otrzymuje sie czysty produkt kry¬ staliczny o barwie jasnozóltej, topniejacy w tem¬ peraturze 118CC. g otrzymanego produktu traktuje sie 400 ml 40 6n kwasu solnego i utrzymuje w stanie wrzenia pod chlodnica zwrotna w ciagu 2Va godziny, po czym chlodzi, odsacza wykrystalizowany kwas ftar Iowy (19 g) i przesacz odparowuje do sucha pod zmniejszonym cisnieniem. Pozostalosc rozpuszcza sie w 50 ml etanolu, dodaje 250 ml eteru i odsa¬ cza wytracony chlorowodorek 3-amino-l-hydroksy- -3-metylobutanonu-2 o wzorze 4. 1 mol chlorowodorku semikarbazydu rozpuszcza sie w mozliwie malej ilosci wody dodajac 1 mol wodoroweglanu sodowego i miesza az do ustania wydzielania sie gazu. Nastepnie dodaje sie porcja¬ mi 1 mol chlorowodorku aminoketonu o wzorze 4 i mieszajac ogrzewa na lazni parowej w ciagu 30 minut, po czym chlodzi i odsacza wykrystalizowa¬ ny chlorowodorek semikatfbazonu o wzorze 3, prze¬ mywa osad etanolem i eterem. Otrzymany piodukt ma temperature topnienia 208°C i stosuje sie go do dalszej fazy procesu bez oczyszczania. 6,8 g tego produktu miesza sie z 6,0 g z 2-amino- -4-chloro-6-hydroksy-5-nitropirymidyny, 10 ml trójetyloaminy i 450 ml etanolu i mieszanine u- trzymuje w stanie wrzenia pod chlodnica zwrotna w ciagu 18 godzin, po czyni ichlodzi i odparowuje do objetosci 200 ml. Po ochlodzeniu odsacza sie; wydzielony osad, otrzymujac 6,0 g semikarbazonu ketonu pirymidynyloaminowego o wzorze 2. Pro¬ dukt ma barwe bezowa i topnieje w temperaturze 206—210°C. PL PL PL PL PL PL PL The subject of the invention is a method for preparing a new 2-amino-4-i(1,1'-dimethyl-3,-hydroxy-acetonyl)-amino-6-hydroxy-5-nitropyrimidine of formula 1. This compound is the starting product for the preparation of 2-amino-4-hydroxy-6-hydroxy-5-methyl-7,7-dimethyl-7,8 - dihydropteridine, which is a valuable bacteriostatic agent. In the method according to the invention, 2-amino-4-(l',l'-dimethyl-3'-hydroxyacetonyl)-amino-6-hydroxy-5-niitropyrimidine is produced by the action of acid on the semicarbazone of the pyrimidinylamino-ketone acid of formula 2. An acid of moderate strength is used for this purpose, in particular an organic acid, e.g. trifluoroacetic acid or benzenesulfonic acid, or a mineral acid, preferably dilute, e.g. dilute hydrochloric acid or sulfuric acid. The reaction is preferably carried out at the boiling temperature of the reaction mixture for a few to several minutes, after which the mixture is cooled, filtered and the filtrate is neutralized, preferably with ammonium hydroxide. The precipitated compound of formula I is filtered off and purified by known methods. The compound of formula II, which is the starting product in the process according to the invention, is a new compound. It is easily prepared by reacting the semicarbazone 3-amino-1-hydroxy-3-methylbutanone-2 or its salt, preferably the hydrochloride of formula 3, with 2-amino-4-halo-6-hydroxy-5-nitropyrimidine. The reaction is carried out in the presence of an acid-binding agent, such as, for example, sodium carbonate or a tertiary amine, e.g., triethylamine. The compound of formula III is also a new compound and is prepared by treating 3-amino-1-hydroxy-3-methylbutanone-2 or a salt thereof, preferably the hydrochloride of formula IV, with semicarbazide or a salt thereof. The reaction is preferably carried out in the presence of a buffer substance, e.g., sodium acetate or sodium carbonate. The compound of formula IV is also a new compound and is prepared by treating 1-hydroxy-3-methyl-3-phthalimidobutanone-2 of formula V with an acid, preferably a strong acid, such as hydrochloric acid, hydrobromic acid or sulfuric acid. The compound of formula 5 is also a new compound and is prepared by treating 1-diazO'-3-phthaloyl:2-amidobutaine of formula 6 with an acid. Dilute mineral acid, especially dilute sulfuric acid, is preferably used as the acid. The compound of formula 6 is also a new compound and is prepared, for example, by reacting diazomethane with N-phthalyl-2-aminobutyric acid chloride, which is a known compound. Preferably, an excess of diazomethane is used, e.g. twice the amount resulting from stoichiometric calculations, in order to bind the acid remaining during the reaction. Example A mixture of 6.0 g of pyrimidinylamine ketone semicarbazone hydrochloride of formula II and 100 ml of 2N hydrochloric acid was boiled under reflux for 10 minutes, then cooled and filtered. Ammonium hydroxide (density 0.880) was added dropwise to the filtrate with stirring until neutral, after which the separated 2-amino-4-(1',1'-dimethyl-3'-hydroxyacetonyl)amino-6-hydroxy-5-nitropyrimidine was filtered off and washed with water, ethanol, and ether. A yellowish-white product is obtained, melting at 218°C. The compound of formula II used as starting material in this example is prepared as follows: An alcohol-free solution of diazomethane in ether, obtained by dissolving 136 g of Diazald in 950 ml of ether, is added dropwise to a mixture containing a solution of 40.9 g of potassium hydroxide in 70 ml of water, 240 ml of diethylene glycol and 70 ml of ether, heated to 65-70°C in a water bath. The resulting diazomethane is distilled off and slowly treated with a solution of 51.1 g of N-phthalyl-2-aminoisobutyric acid chloride in 700 ml of ether. The mixture is shaken and left overnight at room temperature, after which the ether is evaporated under reduced pressure, yielding 1-diazo-3-methyl-3-phthalimidobutan-2-one (VI) as light yellow crystals. 50 g of the resulting product is mixed with 500 ml of 0.5 N sulfuric acid and heated to 80°C, initiating the hydrolysis process. After gas evolution has ceased, the mixture is poured into 1 liter of ice water, the resulting 1-hydroxy-3-methyl-3-phthalimidophosphate-2-one of formula V is filtered off and washed with 50 ml of water, and then recrystallized from aqueous ethanol by adding activated charcoal. A pure, light yellow crystalline product is obtained, melting at 118°C. 1 g of the product obtained is treated with 400 ml of 40 6N hydrochloric acid and heated under reflux for 2 hours. Then the mixture is cooled, the crystallized phthalic acid (19 g) is filtered off, and the filtrate is evaporated to dryness under reduced pressure. The residue is dissolved in 50 ml of ethanol, 250 ml of ether is added, and the precipitated 3-amino-1-hydroxy-3-methylbutan-2-one hydrochloride (4) is filtered off. 1 mole of semicarbazide hydrochloride is dissolved in as little water as possible, 1 mole of sodium bicarbonate is added, and the mixture is stirred until gas evolution ceases. Then 1 mole of aminoketone hydrochloride (4) is added in portions and heated on a steam bath for 30 minutes with stirring. The mixture is then cooled and the crystallized semicarbazide hydrochloride (3) is filtered off, and the precipitate is washed with ethanol and ether. The resulting product has a melting point of 208°C and is used in the next step of the process without purification. 6.8 g of this product is mixed with 6.0 g of 2-amino-4-chloro-6-hydroxy-5-nitropyrimidine, 10 ml of triethylamine and 450 ml of ethanol and the mixture is heated under reflux for 18 hours, then cooled and evaporated to 200 ml. After cooling, the precipitate is filtered off, yielding 6.0 g of pyrimidinylamine ketone semicarbazone of formula II. The product is beige in color and melts at 206-210°C. PL PL PL PL PL PL PL

Claims (1)

1.1.
PL1970166422A 1969-01-28 1970-01-26 Amino pyrimidines[us3635978a] PL87801B1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US79478669A 1969-01-28 1969-01-28

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PL87801B1 true PL87801B1 (en) 1976-07-31

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PL1970138382A PL82983B1 (en) 1969-01-28 1970-01-26 Amino pyrimidines[us3635978a]
PL1970166422A PL87801B1 (en) 1969-01-28 1970-01-26 Amino pyrimidines[us3635978a]

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Application Number Title Priority Date Filing Date
PL1970138382A PL82983B1 (en) 1969-01-28 1970-01-26 Amino pyrimidines[us3635978a]

Country Status (17)

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US (1) US3635978A (en)
JP (1) JPS4813555B1 (en)
AR (1) AR192568A1 (en)
BE (1) BE745104A (en)
BR (1) BR6915073D0 (en)
CA (1) CA959490A (en)
CH (1) CH535249A (en)
DE (2) DE2003859A1 (en)
DK (1) DK140697B (en)
ES (1) ES375933A1 (en)
FI (1) FI50979C (en)
FR (1) FR2034499B1 (en)
GB (5) GB1303171A (en)
HU (1) HU162913B (en)
IL (2) IL39672A (en)
NL (1) NL169880C (en)
PL (2) PL82983B1 (en)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1363064A (en) * 1970-07-27 1974-08-14 Wellcome Found Pyrimidine derivatives as intermediates in the synthesis of pteridines
US3959278A (en) * 1970-07-27 1976-05-25 Burroughs Wellcome Co. Method of synthesis of pteridines
ZA725322B (en) * 1971-08-05 1974-03-27 Wellcome Found Potentiating formulations
GB1454165A (en) * 1972-08-01 1976-10-27 Wellcome Found Biologically active compounds and compositions
GB1453831A (en) * 1972-08-01 1976-10-27 Wellcome Found Biologically active compounds and compositions
GB1451043A (en) * 1972-08-01 1976-09-29 Wellcome Found Biologicylly acitve compounds and compositions
US4036961A (en) * 1972-08-01 1977-07-19 Burroughs Wellcome Co. Pharmaceutical compositions containing pteridines
US4156725A (en) * 1972-08-01 1979-05-29 Burroughs Wellcome Co. Bacteriostatic biologically active compositions
US4073786A (en) * 1973-07-30 1978-02-14 Burroughs Wellcome Co. 2-Amino-4-hydroxy-6-hydroxymethyl-7,7-diethyl-7,8-dihydropteridine and the 7-spirocyclohexyl analogue thereof
JP3181375B2 (en) * 1992-05-30 2001-07-03 株式会社豊夢 Bonding tool, method for bonding structural members using the same, and bonding structure between structural members
JP4780834B2 (en) * 1998-10-22 2011-09-28 フィリップ・ビー・ビー・モヘノ Novel pterin antineoplastic drugs

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2547501A (en) * 1946-12-10 1951-04-03 American Cyanamid Co Method of preparing 2-amino-4-hydroxy-6-methylol pteridine

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Publication number Publication date
FI50979B (en) 1976-05-31
IL39672A (en) 1972-12-29
GB1303171A (en) 1973-01-17
FR2034499A1 (en) 1970-12-11
JPS4813555B1 (en) 1973-04-27
CA959490A (en) 1974-12-17
DE2056569A1 (en) 1971-08-12
BE745104A (en) 1970-07-28
DK140697B (en) 1979-10-29
BR6915073D0 (en) 1973-07-17
GB1303175A (en) 1973-01-17
GB1303173A (en) 1973-01-17
GB1303172A (en) 1973-01-17
US3635978A (en) 1972-01-18
CH535249A (en) 1973-03-31
DE2003859A1 (en) 1971-04-08
GB1303174A (en) 1973-01-17
FR2034499B1 (en) 1973-12-21
IL33783A0 (en) 1970-03-22
IL33783A (en) 1972-09-28
HU162913B (en) 1973-04-28
ES375933A1 (en) 1972-09-01
DE2056569B2 (en) 1979-06-13
DE2056569C3 (en) 1980-02-21
NL7001122A (en) 1970-07-30
NL169880C (en) 1982-09-01
FI50979C (en) 1976-09-10
PL82983B1 (en) 1975-12-31
AR192568A1 (en) 1973-02-28

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